CA2116773C - Triazolylated tertiary amine compound or salt thereof - Google Patents

Abstract

(see figure I) A triazolylated tertiary amine compound represented by general formula (I) or a salt thereof, having an aromatase inhibitory activity and being useful for preventing and treating breast cancer, mastopathy, endometriosis, prostatomergaly, etc., wherein A
represents a single bond, lower alkylene or carbonyl; B
represents lower alkyl, aryl, a 5- or 6-membered heterocyclic group, or a bicyclic fused heterocyclic group; D represents aryl, a 5- or 6-membered heterocyclic group, or a bicyclic fused heterocyclic group; and E
represents 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl or 1H-1,2,3-triazolyl.

Description

Specification TRIAZOLYLATED TERTIARY AMINE
COMPOUND OR SALT THEREOF
Technical Field The present invention relates to novel triazolyl-substituted tertiary amine compounds having an aromatase inhibiting activity useful as medicines.
Background Art Regarding biosynthesis of estrogen in a living body, it is known that an enzyme, aromatase, participates in the final step of the route of the biosynthesis.
Aromatase aromatizes A ring of a steroid with a substrate of androgen to form estrogen. Therefore, by inhibiting this enzyme activity, prevention and curing of various diseases to be caused by estrogen as an exacerbating factor is possible.
On 'the basis of the knowledge, some aromatase inhibiting compounds have heretofore been proposed. As typical examples of them, mentioned are imidazolyl- or triazolyl- or pyridyl-substituted methyl compounds described in Euxopean Patent Laid-Open Nos. 236,940 and 293,978.
However, compounds of the present invention are structurally definitely different from the known compounds in the point that the former have a triazolyl-~~.~.'l'~3 substituted tertiary amino group. Such compounds having a triazolyl-substituted tertiary amino group have not almost been produced up to the present. In particular, any effective method of direct alkylation, especially arylation, of the terminal amino group of the triazolyl group has not been known.
The present invention provides novel triazolyl-substituted tertiary amino compounds which are structurally different from any known compounds and also provides an optimum method of producing them. In addition, the novel compounds were found to have an excellent aromatase inhibiting activity. On the basis of these findings, the present invention has been completed.
Disclosure of the Invention The triazolyl-substituted tertiary amino compounds according to the present invention are represented by the following general formula (I):
/C~
CN-N ( I ) \A-B
wherein A represents a single bond, a lower alkylene group or a carbonyl group;
B represents a lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- or 6-membered heterocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms, or an optionally substituted bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring;
D ring represents an optionally substituted aryl group, an optionally substituted 5- or 6-membered he~terocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms, or an optionally substituted bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring; and E ring represents a 4H-1,2,4-triazole ring, a 1H-1,2,4-triazole ring or a 1H-1,2,3-triazole ring. These definitions apply hereinafter.
Compounds of the present invention will be explained in more detail hereinafter. The term "lower"
as used herein indicates a linear or branched carbon chain having from 1 to 6 carbon atoms, unless otherwise specifically defined.
Therefore, a "lower alkyl group" concretely includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl) group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a 2-~~.~.~'l'l3 methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, an isohPxyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,.3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. Of them, preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group.
A "Lower alkylene group" is a linear or branched carbon chain having from 1 to 6 carbon atoms, concretely including, for example, a methylene group, an ethylene group, a propylene group, a tetramethylene group, a 2-methyltrimethylene group, a 1-ethylethylene group, a pentamethylene group, and a 1,2-diethylethylene group. Of them, preferred are a methylene group and an ethylene group.
The "aryl group" for B or D ring .includes, for example, a phenyl group, a naphthyl group, an anthracenyl group and a phenanthrenyl group; and the "~- or 6-membered heterocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms" for 'the ring includes, for example, a furyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, and a pyradinyl group. The "bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring" includes, for example, a benzothiazolyl group, a benzoxazolyl group, a quinolyl group, an isoquinolyl group, a benzotriazolyl group, and a benzofurazanyl group.
The above-mentioned "aryl group", "5- or 6-membered heterocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms", and "bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring" each may have one or more, preferably 1 or 2, substituents.
As examples of substituents for the groups, there are mentioned a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an aroyl group, an aroyloxy group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a ~1~.~'r'~3 sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group, and a mono- or di-lower alkylsulfamoyl group. Of them, preferred are a halogen atom, a cyano group, a vitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, and a lower alkanoylamino group. More preferred are a halogen atom, a cyano group and a vitro group.
The "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The "lower alkoxy group" includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyJ.oxy (amyloxy) group, an isopentyloxy group, a tart-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, and a hexyloxy group. Of them, preferred axe a methoxy group and an ethoxy group.
The "lower alkoxycarbonyl group" includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, and a pentyloxycarbonyl group; the "lower alkanoyl(oxy) group" includes an acetyl(oxy}
group, a propionyl(oxy) group, a butyryl(oxy) group, a i:~l~i"'r~3 valeryl(oxy) group, and an isovaleryl(oxy) group; and the "lower alkanoylamino group" includes an acetylamino group, a propionylamino group, a butyrylamino group-, valerylamino group, and an isovalerylamino group.
The '~aroyl group" or "aroyloxy group" includes a benzoyl(oxy) group, a 1-naphthylcarbonyl(oxy) group, a 2-naphthylcarbonyl(oxy) group, a thienoyl(oxy) group, a pyrroloyl(oxy) group, and a 2-, 3- or 4-pyridylcarbonyl-(oxy) group.
The meaning of the above-mentioned "lower alkyl group" shall apply to the lower alkyl moiety in the "mono- or di-lower alkylaminocarbonyl group" or the "mono- or di-lower alkylsulfamoyl group". Typical examples of the groups are a methylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl.
group, a propylaminocarbonyl group, a methylsulfamoyl group, a dimethylsulfamoyl group, and a diethylamino-sulfamoyl group.
The "lower alkylsulfonyl group" includes a methylsulfonyl group, an ethylsulfonyl group, a propyl-sulfonyl group, an isopropylsulfonyl group, a butyl-su7.fonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group.
The compounds of the present invention may easily form salts with inorganic acids or organic acids, and the salts also have an aromatase inhibiting activity like the corresponding free bases. As preferred salts, for example, mentioned are inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, nitrates and phosphates; as well as organic acid salts such as oxalates, fumarates and tartarates.
Depending upon the kinds of the substituents in the compounds, the compounds may also form pharmaceutic-ally acceptable salts with alkali metals or alkaline earth metals (e.g., sodium, potassium, magnesium or calcium salts) or form salts with organic amines such as ammonia or triethylamine.
Depending upon the kinds of the substituents in the compounds, the compounds may have an asymmetric carbon atom and they include all isomers such as optical isomers and diastereomers based on the asymmetric carbon atom.
In addition, there are various hydrates, solvates and tautomers of the compounds of the present invention, as the case may be. The present invention also includes the isolated hydrates, solvates or tautomers as well as mixtures of them.
The compounds of the present invention can be produced by various methods, on the basis of the g _ ~l~~i~l'~3 characteristics of the basic skeleton thereof and also those of the kinds of the substituents therein. Some typical methods are mentioned below.
First Production Methode X C~ C D
(m) C~' - ~I2 -~ E N - NH
(IV) (II) X-A-B _ (V) X A - B
(V) C D
E N-NH X - C D
(VI) ~ E N - N
(IL() C \ (I) \A-B
wherein X represents a halogen atom, an arylsulfonyloxy group, or a lower alkylsulfonyloxy group.
Production of the intended compound (I) from an N-aminotriazole (II) may be effected by the above-mentioned two routes. fihe reaction in each step in the routes is alkylation or acylation of the amino group, which may be conducted in the same manner.
- g -'?1~.~'1'~3 Specifically, in accordance with the above-mentioned reaction, reaction-corresponding amounts of starting compounds are brought into contact with each other, fox example, in a solvent which is inert to the reaction, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, acetone or methyl ethyl ketone, in the presence of a base. As the base, usable are, for example, sodium hydride, sodium amide, n-butyl lithium, potassium t--butoxide, sodium, sodium methoxide, sodium ethoxide, sodium hydroxide and potassium hydroxide. The reaction may be effected with ease at room temperature.
The arylsulfonyloxy group in this case includes, for example, a phenylsulfonyloxy group and a benzylsulfonyloxy group; and the lower alkylsulfonyloxy group is a sulfonyloxy group substituted by a lower alkyl group, including, for example, a methylsulfonyloxy group, an ethylsulfonyloxy group and a propylsulfonyloxy group.

~.~i~~l'~3 Second Production Method, CN-~a OHC-A1-B (B) (V~) CN-N
~Ai_B
E N-NH
~-.Al-B
(X() X-C-D
~~//(IQ) G
l E N-N
-.Al-g ( I a) wherein A1 represents a lower alkylene group in which the number of methylene groups is smaller than A by one. The same definition applies hereinafter.

In accordance with the method, an N-aminotriazole (II) is reacted with an aldehyde compound (VII) to give the corresponding Schiff base (IX), this base (IX) is reduced to give a compound (XI), and the compound (XI) is alkylated or acylated in the same manner as in the first production method to obtain the intended product (Ia). The reaction of forming the Schiff base is effected by azeotropic dehydration or the like, in a solvent,.such as methanol, ethanol or the like alcohol or benzene or 'toluene, in the presence of an acid catalyst.
The reduction may be effected by an ordinary method, using, for example, sodium borohydride, lithium borohydride or sodium borocyanide hydride. As the reaction solvent, usable is an alcohol such as methanol or ethanol, or an organic solvent such as acetic acid, or water, or a mixed solvent of. them. In the reduction, the Schiff base formed may not be isolated but a reducing agent may be added to the Schiff base-containing reaction solution to conduct the reduction.

~~~~3~~~
Third Production Method:
R' CN-N ECN-N
\A-Bi R 1 (V>Q) (XVI) Reduction Reduction ~C~ NHZ R 1 E N-N
CN N (XIV) ~ \ A - B 2 (XVII) R~
1) Sandmeyer's Reactin 1) Sandmeyer's Reactin 2) Removing the 2) Removing the protecting group protecting group ~Cy y CN N-~ A. - B3 (XVIII) CN N
H
X-A-B (V) X-C~ (L11) ~ /. C\~ y' ~ / C
E N-N ~ l E N-N
\ ,~ _ B ~.-~ \ A _ B a (I b) (I c) wherein R1 represents an amino-protecting group; Y
represents a halogen atom; B1 and D1 each represent an aryl group, a 5-membered or 6-membered heterocyclic group ~'~.I~Y~''~3 or a bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring, which is substituted by a vitro group; BZ represents an aryl group, a 5-membered or 6-membered heterocyclic group or a bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring, which is substituted by an amino group; and B3 represents an aryl group, a 5-membered or 6-membered heterocyclic group or a bicyclic fused heterocyclic group composed of the preceding hetero ring and a benzene ring, which is substituted by a halogen atom. These definitions apply hereinafter.
In accordance with the method, halogen-substituted compounds of a general formula (Ib) or (Ic) of the present invention are obtained.
Thus, a compound of a general formula (XIII) or (XVI) is reduced to give an amino compound of a general formula (XIV) or (XVII); the amino compound is subjected to Sandmeyer's reaction where a halogen atom is introduced and the protecting group is removed, to give a compound of a general formula (XV) or (XVIII), and this compound is reacted with a compound (V) or (III) to give the intended compound (Ib) or (Ic), respectively.
Reduction of the compound of formula (XIII) is effected by an ordinary method of chemical reduction or catalytic reduction.
As a reducing agent to be used in chemical reduction, suitable are metals such as tin, zinc or iron.
As catalytic reduction, conventional catalysts are used, including, for example, a platinum catalyst such as platinum or platinum oxide, a palladium catalyst such as palladium black or palladium oxide, and a nickel catalyst such as Raney nickel*
As a solvent for the reduction reaction, any conventional solvent can be used, including, for example, methanol, ethanol, propanol, ethyl acetate and acetic acid. Protection of the nitrogen atom of the compound of formula (XIII) or (XVI) is effected with a conventional acyl-protecting group such as acetyl or benzoyl group.
Introduction of the protecting group may be effected by reaction of the compound with acetic anhydride, acetyl chloride or benzoyl chloride, in the presence of a base such as sodium acetate, pyridine, picoline, lutidine, trimethylamine or triethylamine. As a solvent for the reaction, usable are dichloromethane, dichloroethane, chloroform, benzene or toluene. The reaction may also be effected in the absence of a solvent.
Next, the thus obtained compound (XIV) or (XVII) is subjected to Sandmeyer's reaction so that a halogen atom is introduced thereinto and then the *-trademark ~~~~'l rl3 protecting group is removed to yield a compound (XV) or (XVIII). Sandmeyer's reaction may be effected by any ordinary method, for example, using cuprous chloride;
cuprous bromide or cuprous iodide and hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid. As a solvent for the reaction, usable are water, acetone, dioxane, and tetrahydrofuran. Removal of the protecting group may be effected by acid hydrolysis with dilute hydrochloric acid or dilute sulfuric acid. To the reaction of the thus obtained compound (XV) and a compound (V) or (ITI), the same way as mentioned in the first production method and the second production method may apply.
Other Production Methods:
(1) Where the compounds of the present invention has an amino group as a substituent, they are obtained by reducing the compound of 'the present invention having a corresponding nitro group. The reaction is conversion of a substituent, to which 'the same reduction as that in the third method may apply.
(2) Where the compounds of the present invention has a lower alkanoylamino group as a substituent, they may be obtained by reacting the compound of the present invention having a corresponding amino group with acetic anhydride or the like by an ordinary method.
(3) Where the compounds of the present invention has a benzotriazole group in the substituent B
or as the ring D, they may be obtained by reducing the compound of the present invention having an amino group (or a mono-substituted amino group) and a nitro group as the adjacent substituen-ts in the phenyl group, at the nitro group to convert it into an amino group, followed by reacting the reduced compound with sodium nitrite, potassium nitrite or the like to effect ring closure to form a benzotriazole group in the compound.
The compounds of the present invention thus prepared can be isolated and purified by any conventional methods, for example, by extraction, precipitation fractional chromatography, fractional crystallization, recrystallization or the like. Salts of the compounds of the present invention can be produced by subjecting the free base to ordinary salt-forming reaction to give a desired salt thereof.
Tndustrial Applicability The compounds of the present invention have a function of inhibiting an aromatase, which participates in estrogen biosynthesis from androgen. Therefore, the compounds of the present invention are useful for treatment of the diseases in which estrogen is _ 17 participated as an exacerbating factor, such as breast cancer, mastopathy, endometriosis, prostatomegaly, hysteromyoma, and cancer of uterine body.
References:
Pharmacia, 26 (6) 558 (1990);
Clinical Endocrinoloay, 32 623 (1990);
J. Steroid Biochem. Molec. giol., 37 (3) 335 (1990);
Br. J. Cancer, 60 5 (1989);
Endocrinoloay, 126 (6) 3263 (1990);
The Journal of Pharmacoloay and Experimental Therapeutics, 244 (2) (1988);
Endocrinol. Japan, 37 (5) 719 (1990);
Steroids, 50 1 (1987).
Experimental Methods:
Pharmacological effects of the compounds of the present invention were identified by the methods mentioned below.
(1) In vitro inhibition of aromatase:
(a) Inhibition of aromatase obtained from rat ovary:
The activity was measured in accordance with the method described in J. Biol. Chem., 249 5364 (1974).
The TCso value of the test compound on aromatase inhibition was determined based on inhibition of 'HBO to be released from [1,2-3H] androstenedione in rat ovarian microsomes.

(b) Inhibition of aromatase obtained from human placenta The activity was measured in accordance with the method described in Endocrine Research, 16 (2) 253 (1990).
The inhibition activity of the compound was determined based on the inhibition of 3I-IZO to be released from [1,2-3H] androstenedione in human placenta microsomes.
(2) In vivo inhibition of aromatase activity To female Wister rats each weighing 60 g (not matured), were injected subcutaneously 100 It3/rat of mare's serum gonadotropin (PMSG). After 72 hours, a test compound dissolved in 0.5 ml of a 20~ polyethylene glycol aqueous solution was administered to the rat. As a control, a 20~ polyethylene aglycol aqueous solution was administered. Three hours after the administration, the rats were sacrificed by decapitation and bleeding and their ovaries were removed and the estradiol content of the ovaries were measured by RIA.
(3) Antitumor activity:
The antitumor activity of a 'test compound to breast carcinoma was measured in a dimethylbenzanthracene (DMBA)-induced female Sprague-Dawlay rat tumor.

(4) In vitro and in vivo inhibition of aldosterone production:
(a) In vitro inhibition of aldosterone production:
The activity was measured in accordance with the method described in J. j7et. Pharmacol. Therap., 11 345 (1988). The inhibition activity of the test compound was determined based on the 5.nhibition of aldosterone production produced by stimulation of first-generation of rat adrenal cultured cells by,ACTH. The amount of aldosterone was measured by RIA.
(b) In vivo inhibition of aldosterone production in rats:
The inhibitory activity was measured in accordance with the method described in J. Steroid Biochem., 34 567 (1989). The inhibitory activity of a test compound was determined based on inhibition of 'the blood aldosterone to be increased by stimulation by ACTH
in rats. The amount of aldosterone was measured by RIA.

(5) In vitro inhibition of cortisol production:
The inhibitory activity was measured in accordance with the method described in Endocrinoloay.
114 (2) 486 (1984). The inhibitory activity of a test compound was determined based an inhibition of the cortisol production produced by stimulation of first-generation of rabit adrenal cultured cells by ACTH. The amount of cortisol was measured by RIA.
Results of Experiments:
The results of the experiments mentioned above are shown below.
1. In vitro inhibition of aromatase in human placenta microsomes:
Activity ICSO value for ex vivo inhibition of aromatase from human placental microsomes was obtained in accordance with she above-mentioned experimental method (1-b), and the .results obtained are shown in Table 1.

Test Compound ICs~-Compound of Example 10 0.11 nM
Compound of Example 12 0.03 nM
Compound of Example 15 0.13 nM
Control Compound 0.41 nM
Control Compound: Compound of Example 20 (b) in European Patent Laid-Open No. 236,940. The same shall apply hereinafter.
As is obvious from the results above, the compounds of 'the present invention exhibited a signifi-cantly higher in vitro inhibition of aromatase in human placental microsomes than the control compound.

2. Selectivity of In vitro inhibition of rat ovarian aromatase and in vitro aldosterone production in rat:
IC;o values for in vitro inhibition of rat aromatase and ex vivo inhibition of rat aldosterone production were measured in accordance with the above-mentioned experimental methods (1-a) and (4-a), respec-tively. The selectivity was obtained by calculation anal shown in Table 2. The selectivity indicates a ratio of IC;o value for rat aldosterone production to IC;o value for rat aromatase.

IC;o of Compound Control Test Compound of Example 15 Compound Rat aromatase 0.37 nM 1.83 nM
inhibitory activity (A) Rat aldosterone 2.25 ~M 3.18 ~M
inhibitory activity (B) Selectivity (B/A) 6:L00 1700 As is obvious from the results above, the compound of the present invention also exhibited a significantly higher rat aromatase in vitro inhibitory activity than the control compound. In addition, 'the both compounds exhibited almost the same in vitro rat aldosterone production inhibitory activity.
Therefore, the selectivity of the in vitro aromatase inhibitory activity to 'the in vitro aldosterone production inhibitory activity (B/A) of the compound of Example 15 of the present invention was 6100, arid that of the control compound was 1700. This means that the -compound of the present invention has an extremely small influence on the aldosterone producing system and therefore is a highly selective aromatase inhibitor.
Aldosterone which is known as a mineral corticoid has some biological effects. It is known -that inhibition of aldosterone production causes some harmful side effect, such as depression of blood pressure and orthostatic hypotension due to decrease of the body fluid as well as abnormal electrolyte balance by lost of potassium ions foam the body. Accordingly, since the compound of the present invention is an aromatase inhibitor with high enzyme selectivity with less inhibition activity of aldosterone production, it is expected to be a highly safe compound with few harmful side effects.
3. In vivo inhibition of aldosterone production in rats:
By the above-mentioned experimental method (4-b), aldosterone production inhibitory activity in rats was measured. Where l0 mg/kg of the test compound was administered to each of five rats, inhibition of the aldosterone production in -the rats was 37~, which is significant in comparison with the control.

On the other hand, where 100 mg/kg (10 times of the above case) of each of the compounds of Examples 10, 12 and 15 of the present invention was administered to each of five rats (as test group), they did not inhibit aldosterone production significantly. The statistical significance of value was analyzed by using one-way ANOVA. The results mean that the compounds of the present invention are highly safe compounds with few harmful side effects also in the in vivo test as well.
4. In vitro inhibition of cortisol production in rabit:
ICso value of the compounds for in vitro inhibition of. cortisol production was obtained by the above-mentioned experimental method (5), and the results obtained axe shown in Table 3.

Test Compound ICs, Compound of Example 10 7.0 ~M
Compound of Example 15 4.0 ~M
Control Compound 1.6 uM
As is obvious from the results above, it is noted that the compounds of the present invention exhibited a significantly lower in vitro cortisol production inhibitory activity in rabbit than the control compound. It is known that the .
inhibition of cortisol production causes various harmful side effects such as depression of blood sugar, nervus system function disorders, increase of stress and increase of inflammation. Accordingly, since the compounds of the present invention have a weak cortisol inhibiting activity, they are expected to be compounds having less harmful side effects than the control compound.
5. In vivo inhibition of aromatase activity:
Aromatase activity inhibitory activity in rat was measured by the above-mentioned experimental method (2). The minimum effective dose of the compound of 'the present invention was 0.001 mg/kg.

6. Antitumor activity:
In accordance with the above-mentioned experi-mental method (3), compounds of the present invention cause suppression or regression of existing tumors at daily oral doses of about 0.04 to 1.0 mg/kg.

7. Metabolism:
Where 3 mg/kg of the compound of Example 15 of the present invention was orally administered to 'test rats, the maximum value (Cmax) of the concentration of the non-changed compound in the plasma was 2.88 ug/ml and the extinction half time (Tl~z) was 11 hours. From the :\
11~"~'~3 results, it is understood that the compound of the present invention has an excellent oral absorbability and that the effect of -the absorbed compound lasts long.
Thus, the compound has a good profile as a medicine.
Where the compounds of formula (I) and their non-toxic salts or hydrates are used for the above-mentioned objects, they are generally administered orally or parenterally. The amount of them fo-r dose varies, in accordance with the age, body weight and condition of patients, as well as the curing effect, administration route and treating time with the compounds. In general, it is from 0.1 to 100 mg/adult/day, preferably :From 1 to mg/adult/day, fax oral administration all at a time or as parts divided for several administrations a day; or it is from 0.1 to 100 mg/.adult/day .for parenteral administration all at a -time or as parts divided for several administrations or for continuous intravenous injection for from 1 to 24 hours a day. Since the amount of the compounds of the present invention for dose varies, depending upon various conditions, a smaller dose 'than the range defined above would often be satisfactory in some cases.
As a solid composition for peroral administra-tion of the present invention, usable are tablets, powder and granules. In the solid composition of the kind, one ~ ~. ~. o '~ '~ ~
or more active substances are blended with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, fine crystalline cellulose, starch, polyvinyl pyrrolidone and magnesium aluminate metasilicate. The composition may optionally contain any other additives than 'the inert diluent, for example, lubricant such as magnesium stearate, disintegrator such as calcium glycolate cellulose, stabilizer such as lactose, and dissolution aid such as glutamic acid or aspartic acid, by an ordinary method. Tablets and pills may optionally be coated with a film of a gastric-soluble or enteric-soluble substance, such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate.
A liquid composition for oral administration of the present invention includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir and it contains a conventional inert diluting agent such as pure water or ethanol. The composition may further contain, in addition to the inert diluting agent, other auxiliary agents such as a wetting agent or a suspending agent, as well as a sweetener, a flavor, an aroma and an antiseptic agent.
An injection for parenteral administration of the present invention includes sterilized aqueous or non-~i~.~~~'~3 aqueous solution, suspension and emulsion. The aqueous solution and suspension contain, for example, an injectable distilled water and a physiological saline.
The non-aqueous solution and suspension contain, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80, etc. The composition of the kind may further contain other auxiliary additives such as an antiseptic agent, a wetting agent, an emulsifier, a dispersing agent, a stabilizer (e.g., lactose), a dissolution aid (e. g., glutamic acid, aspartic acid), etc. The composition is sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a microbicide thereto, or by light irradiation. As the case may be, a sterilized solid composition is first prepared, and it may be dissolved in a sterilized water or sterilized injectable solvent to give an injection before use.
Best mode for carrying out the invention Next, the present invention will be explained in more detail by way of the following examples. Prepara-tion of the starting compounds to be used 9.n the examples is disclosed as referential examples.
_ 28 -~.~~ ~'~~~

-N- , ~'CN
80 Milliliters of benzene was added to 8.4 g of 4-amino-1,2,4-triazole, 13.1 g of p-cyanobenzaldehyde and 1.9 g of p-toluenesulfonic acid monohydrate and the mixture was heated under reflex for 4 hours under azeotropic dehydration condition. After cooled, the crystals as precipitated out were taken out by filtration to quantitatively obtain 4-[(4-cyanobenzylidene)amino]-4H-1,2,4-triazole.
Mass Spectrometry (m/z): 198 (M++1) 1-NH~ CN
2.52 Grams of 4-amino-1,2,4-triazole was added little by little to a dimethylsulfoxide suspension of 1.2 g of sodium hydride at room temperature. After stirred for 3 hours at room temperature, 1.21 g of 4-fluorobenzonitrile was added thereto all at a time, and stirring was continued for further one hour. Water was added to the reaction solution, and the mixture was then ~~.I~"l'~~
extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. 'The crystals obtained were washed with ethyl acetate to give 1.09 g of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 6.57 (2H, d, J=9Hz), 7.69 (2H, d, J=9Hz), 8.83 (2H, s) Mass Spectrometry (m/z): 185 (M~") In the same manner as in Referential Example 2, the following compound was obtained.
N~1-NH~NO Z
~/N
4-[(4-Nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-amino-1,2,4-triazole and 4-fluoronitrobenzene Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 6.53-6.70 (2H, m), 8.08-8.31 (2I-I, m), 8.88 (2I-I, s), 10.52 (1H, s) Mass Spectrometry (m/z): 205 (M~") :a.:: .

In the same manner as in Referential Example 2, the following compound was obtained.
N~ ~~ CN
1-[(4-Cyanophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-amino-1,2,4-triazole and 4-f luorobenzoinitrile Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 6.56 (2H, d, J=9Hz), 7.70 (2H, d, J=9Hz), 8.18 (1H, s), 8.82 (1H, s), lp.sl (1H, brs) Mass Spectrometry (m/z): 185 (M+) In 'the same manner as in Referential Example 2, the following compound was obtained.
N~~-NH~NOz 1-[(4-Nitrophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-amino-1,2,4-triazole and 4-fluoronitrobenzene Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 6.59 (2H, d, J=9Hz), 8.16 (2H, d, J=9Hz), 8.20 (1H, s), 8.85 (1H, s), 10.80 (lI-x, s) Mass Spectrometry (m/z): 205 (M+) N~
NON°NH
CN
2.28 Grams of sodium borohydride was added gradually to a suspension of 9.85 g of 4-[(4-cyano-benzylidene)amino]-4H-1,2,4-triazole obtained in Referential Example 1 in 100 ml methanol under ice-cooling. The reaction mixture was stirred at the same temperature for 1 hour, arid the solvent was removed by distillation under reduced pressure. Water and sodium chloride were added to the residue successively for salting-out, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, and crude crystals from the chloroforzn/methanol (15:1) eluate were washed with chloroform to give 4.2 g of 4-[(4-cyano-benzyl)amino]-4H-1,2,4-triazole.
Physicochemical properties: -Mass Spectrometry (m/z): 199 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 4.31 (2H, d, J=4Hz), 7.29 (1H, t, J=4Hz), 7.51 (2H, d, J=9Hz), 7.82 (2H, d, J=9Hz), 8.48 (2H, s) ~2 N~ - N
~Br A catalytic amount of Raney nickel*was added to 50 ml of an ethanol solution containing 3.74 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl) amino]-4H-1,2,4-triazole, and the mixture was stirred for about 2 hours in the presence of hydrogen gas at room temperature.
After the catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1.1 g of 4-[N-(4-amino-phenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from *-trademark ~~~.~~1'~3 the chloroform/methanol (50:1) eluate.
Mass Spectrometry (m/z): 344 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 4.71 (2H, s), 4.98 (2H, br), 6.52 (2H, d, J=9Hz), 6.85 (2H, d, J=9Hz), 7.26 (2H, d, J=9Hz), 7.48 (2H, d, J=9Hz), 8.73 (2H, s) CN
N
CN
0.3 Gram of 4-((4-cyanophenyl)amino]-4H-1,2,4-triazole obtained in Referential Example 2 was added little by little to a suspension of 65 mg of sodium hydride in 5 ml of N,N-dimethylformamide at room temperature. After completion of the addition, the reaction mixture was stirred at 50°C for 30 minutes and then cooled. 5 Milliliters of an N,N-dimethylformamide solution conta3.ning 0.20 g of 4-fluorobenzonitrile was added dropwise thereto. After addition, the reaction mixture was stirred at 100°C .f.or 5 hours, and the solvent was removed by distillation under reduced pressure.
Water was added to the residue, and the mixture was then extracted with chloroform. The chloroform layer was - 34 _ ~~~~'~"'l~
washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation.
The residue was purified by silica gel column chromatography, and crude crystals were obtained from the chloroforzn/methanol ( 100:1 ) eluate.
These crude crystals were recrystallized from ethyl acetate to give 0.28 g of 4-[bis(4-cyanophenyl)-amino]-4H-1,2,4-triazole.
Elementary Analysis ( for Cl6HioNs ) C (~) H ($) N ('-k) Calculated: 67.13 3.52 29.35 Measured: 66.92 3.62 29.23 Mass Spectrometry (m/z): 286 (M'") Nuclear Magnetic ~tesanance Spectrum (CDC13, TMS
internal standard) 8 : 7 . 04 ( 4H, d, J=9Hz ) , 7 . 69 ( 4H, d, J=9I-Iz ) , 8.44 (2H, s) Tn the same manner as in Example 2, the following compound was obtained.
CN
N~
~NOa ~~.~.~j~~
4-[N-(4-cyanophenyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-fluoronitrobenzene Elementary Analysis (for C15H1oNs~z) G (~) H (~) N (~) Calculated: 58.82 3.29 27.44 Measured: 58,79 3.46 27.37 Mass Spectrometry (m/z): 307 (M++1) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) &: 6.98-7.16 (4H, m), 7.72 (2H, d, J=9Hz), 8.26 (2H, d, J~9Hz), 8.46 (2I3, s) Tn the same manner as in Example 2, the following compound was obtained. .
N~ -~ Me CN
4-[N-(4-cyanophenyl)-N--methylamino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4I-T-1,2,4-triazole and methyl iodide ~~.~L~'l'~3 Elementary Analysis (for CIOH~Ns) C (~) H ($) N ($) Calculated: 60.29 4.55 35.15 Measured: 60.24 4.66 35.12 Mass Spectrometry (m/z): 199 (M+) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 8: 3.56 (3H, s), 6.60 (2H, d, J=9Hz), 7.60 (2H, d, J=9Hz), 8.41 (2H, s) Tn the same manner, as in Example 2, the following compound was obtained.
N~_ N
CN
4-(N-(4-cyanophenyl)-N-propylamino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and methyl iodide Elementary Analysis (fox CzzHl3Ns) C (~) H ('k) N
Calculated: 63.42 5.77 30.82 Measured: 63.41 5.82 30.77 Mass Spectrometry (m/z): 227 (M~), 198 ~~.~.~'~r13 Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 6: 1.03 (3H, t, J=7Hz), 1.45-1.76 (2H, m)', 3.67 (2H, dd, J=7Hz, J=7Hz), 6.54 (2H, d, J=9Hz), 7.56 (2H, d, J=9Hz), 8.33 (2H, s) In the same manner as in Example 2, the following compound was obtained.
CN
N~I rf CN
4-Cyano-N-(4-cyanophenyl)-N-(4H-1,2,4-triazol-4-yl)-benzamide Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-cyanobenzoyl chloride Elementary Analysis (for CI~I-IlpN6O) C ($) H (~) N (~) Calculated: 64.96 3.21 26.74 Measured: 64.81 3.35 26.72 Mass Spectrometry (m/z): 314 (M+) '> ~.1~"~~13 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 7.61 (2H, d, J=9Hz), 7.77-7.99 (6H, m)', 9.13 (2H, s) Tn the same manner as in Example 2, the following compound was obtained.
CN
N%'~
N~- NOz NOz 4-[N-(4-cyanophenyl)-N-(2,4-dinitrophenyl)amino]-4H-1,2,4-triazo1e Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 2,4-dinitrofluorobenzene Elementary Analysis ( for C~r~HgN7O6 ) C (~) H (~) N
Calculated: 45.29 2.44 ?.6.41 Measured: 45.25 2.55 26.40 Mass Spectrometry (m/z): 371 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) s: 6.82 (2H, d, J=9Hz), 7.95 (1H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.77. (1H, q, J=9Hz), 8.95 (1H, d, J=3Hz), 9.21 (2H, s) s In the same manner as in Example 2, 'the follow-ing compound was obtained.
NOZ
N~
~NOZ
4-(Bis(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-((4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-fluoronitrobenzene Elementary Analysis ( for C1,,H1oN~0,, ) C (~) H (~) N (~) Calculated: 5:1.54 3.09 25.76 Measured: 51.59 3.14 25.80 Mass Spectrometry (m/z): 326 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 7.24 (4H, d, J=9Hz), 8.30 (4H, d, J=9Hz), 9.28 (2H, s) t CN
Me N~ _ N
i~
N
(i) The same process as in Example 2 was repeated, except that 4-fluoro-2-methylaminonitrobenzene was used in place of 4-fluorobenzonitrile, to give 4-[N-(4-cyanophenyl)-N-[(3-methylamino-4-nitro)phenyl]amino]-4H-1,2,4-triazole.
Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 8: 3.16 (3H, s), 7.23 (2H, d, J=8Hz), 7.75 (2H, d, J=9Hz), 7.80 (2H, s), 8.13 (2H, d, - J=9Hz), 8.87 (2H, s) Mass Spectrometry (m/z): 335 (M+) (ii) 30 Milliliters of methanol and 1 g of Raney nickel were added to 1..8 g of 4-[N-(4-cyanophenyl)-N-[(3-methylamino-4-nitro)phenyl)amino]-4H-1,2,4-triazole as obtained in the previous (i) and the mixture was subjected to catalytic reduction in a hydrogen atmosphere under normal pressure. After the Raney nickel*-i~as removed and the solvent was removed by distillation under reduced pressure, the intended 4-[[N-(4-amino-3-methyl-*-trademark amino)phenyl]-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole was quantitatively obtained. This was dissolved in 30 ml of 6 N hydrochloric acid, and 2 ml of an aqueous solution of 0.37 g of sodium nitrite was added dropwise to the reaction mixture at 'the 'temperature below 5°C. After addition, the reaction mixture was stirred at the temperature below 5°C fox 30 minutes and then made alkaline with an aqueous sodium hydroxide solution. This was extracted with ethyl acetate, -the organic layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, and crude crystals were obtained from the ethyl acetate/methanol (100/1) eluate. These crude crystals were recrystallized from ethyl acetate to give 0.17 g of 6-[N-(4-cyano-phenyl)-N-(4H-1,2,4-triazol-4-yl)amino]-1-methyl-1H-benzotriazole.
Nuclear Magnetic Resonance Spectrum (CDCl3 +
DMSO-d5, TMS internal standard) 8: 2.81 (3H, s), 6.75 (2H, d, J=9Hz), 7.36 (1H, dd, J=9Hz, J=2Hz), 7.59 (1H, d, J=2Hz), 7.63 (1H, d, J=9Hz), 8.11 (2H, d, J=9Hz), 8.73 (2H, s) Mass Spectrometry (m/z): 316 (M~), 220 ExAMPLE 10 NOZ
N~-N~"
~NOZ
To a suspension of 0.37 g of 4-[(4-nitro-phenyl)amino]-4H-1,2,4-triazole obtained in Referential Example 3 in 20 ml of 2-butanone were successively added 0.83 g of potassium carbonate anhydride., 1.30 g of p-nitrobenzyl bromide and a catalytic amount of sodium iodide, at roam temperature, and the reaction mixture was then heated under reflux for about 2 hours. After cooled, the solvent was removed by distillation under reduced pressure, and a proper amount of water was added to the residue, which was then extracted several times each with ethyl acetate. The ethyl acetate layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue formed was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals thus obtained were recrystallized from ethanol to give 0.28 g of 4-(N-(4-nitrobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

-\
'> ~. ~. i~ S ~ ~
Elementary Analysis ( for C15H1zN604 ) c (~) H (~) N (~) Calculated: 52.94 3.55 24.?0 Measured: 52.94 3.62 25.02 Mass Spectrometry (m/z): 340 {M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.33 (2I-I, s), 6.77 {2H, d, J=9Hz), 7.66 (2H, d, J=9Hz), 8.20 (4H, d, J=9Hz), 8.93 (2H, s) Tn the same manner as in Example 10, the following compound was obtained.
CN
N
~'"N
RCN
4-[N-(4-cyanobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino-4H-1,2,4-triazole and 4-cyanobenzyl bromide Mass Spectrometry (m/z): 300 (M+) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 6: 4.98 (2H, s), 6.64 (2H, d, J=9Hz), 7.26,-7.74 (6H, m), 8.20 (2H, s) EX.~MPLE 12 NON ~ N
Ney ~Br 8 Milliliters of acetonitrile was added to 0.63 g of 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole, 0.82 g of 4-bromobenzyl bromide and 0.62 g of anhydrous potassium carbonate and the mixture was stirred for 3 hours at zoom temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue obtained, which was then extracted with chloroform. ~fhe chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography 'to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from acetone to give 0.71 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

~' \
Melting Point: 241°C
Elementary Analysis ( for ClSHizBrN50z ) C (~) H (~) N (~) Br (~) Calculated: 48.15 3.23 18.72 21.35 Measured: 48.21 3.1? 18.97 22.50 Mass Spectrometry (m/z): 374 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 5.12 (2H, s), 6.79 (2H, d, J=9Hz), 7.29 (2H, d, J=9Hz), 7.54 (4H, d, J=9Hz), 8.19 (2H, d, J=9Hz), 8.84 (2H, s) Tn the same manner as in Example 10, the following compound was obtained.
NOZ

4-[N-(4-methylbenzyl)--N-(4-nitrophenyl)amino)-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-methylbenzyl bromide _ 46 -Elementary Analysis (for Cl6HisNs~z) C (~) H (~) N
Calculated: 62.13 4.89 22..64 Measured: 61.87 5.00 22.43 Mass Spectrometry (m/z): 309 (M+) Nuclear Magnetic Resonance Spectrum (CDCT3, TMS
internal standard) 6: 2.34 (3H, s), 4.90 (2H, s), 6.68 (2H, d, J=6Hz), 7.08 (2H, d, J=8Hz), 7.16 (2H, d, J=8Hz), 8.10 (2H, s), 8.19 (2H., d, J=6Hz) EXAMPhE 14 Tn the same manner as in Example 10, the following compound was obtained.
NO z N
~,~'''N
~ OCH3 4-[N-(4-methoxybenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and p-methoxybenzyl chloride _ 47 _ Elementary Analysis ( for C16H15N5~3 ) C (~S) H (~) N ($) Calculated: 59.07 4.65 21.53 , Measured: 59.05 4.61 21.50 Mass Spectrometry (m/z): 325 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 3.73 (3H, s), 5.04 (2~I, s), 6.76-6.92 (4H, m), 7.22 (2H, d, J=9Hz), 8.19 (2H, d, J=9Hz), 8.75 (2H, s) CN
NON ~ N
N~
Br 40 Milliliters of acetonitrile was added to 3.15 g of 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole, 4.25 g of 4-bromobenzyl bromide and 3.52 g of anhydride potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue formed, which was then extracted with chloroform. The chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, _ 4g ._ and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from ethanol to give 3.92 g of 4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Melting Point: 203°C
Elementary Analysis (.for C16H1zBrN5) C (~) H (~) N (~) Br Calculated: 54.26 3.41 19.77 22.56 Measured: 53.96 3.48 19.72 22.65 Mass Spectrometry (m/z): 354 (M+) Nuclear riagnetic Resonance Spectrum (DMSO-db, TMS
internal standard) S: 5.06 (2H, s), 6.75 (2H, d, J=9Hz), 7.27 (2H, d, J=9Hz), 7.53 (2H, d, J=9Hz), 7.75 (2H, d, J=9I3z), 8.81 (2H, s) In the same manner as in Example 10, the following compound was obtained.
NOz N~
N
5' ~~.a.~~~'~3 4-[N-(4-nitrophenyl)-N-(4-thiazolylmethyl)amino]-4H-1,2,4-triazo1e Starting Compounds: 4-[(4-nitrophenyl)]amino-4H-1,2,4-triazole and 4-(chloromethyl)thiazole Elementary Analysis ( for ClzH1oN60zS ) C (~) H (~) N (~) S
Calculated: 47.68 3.33 27.80 10.61 Measured: 47.51 3.45 27.75 10.45 Mass Spectrometry (m/z): 302 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-dfi, 'rMS
internal standard) 6: 5.28 (2H, s), 6.77 (2H, d, J=9Hz), 7.77 (1H, brs), 8.17 (2H, d, J=9Hz), 8.80 (2H, s), 9.12 (1H, brs) In the same manner as in Example 10, the following compound was obtained.
NOz N~_ N
'~J'~ F
4-[N-(4-fluorobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)]amino-4H-1,2,4-triazole and p-fluorobenzyl bromide Elementary Analysis ( for ClSHizFNsOz ) C (~) H (~) N (~) F (~) Calculated: 57.51 3.86 22.35 6.06 Measured: 57.44 3.~8 22.37 5.85 Mass Spectrometry (m/z): 313 (M'") Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 5.12 (2H, s), 6.81 (2H, d, J=9Hz), 7.05-7.46 (4H, m), 8.20 (2H, d, J=9Hz), 8.81 (2H, s) Tn the same manner as in Example 10, the following compound was obtained.
NOz N~_ N
~ C1 4-[N-(4-chlorobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and p-chlorobenzyl bromide Elementary Analysis (for ClSHizC1N502) C ($) H (~) N (~) C1 (~) Calculated: 54.64 3.67 21.24 10.75' Measured: 54.59 3.85 21.13 10.72 Mass Spectrometry (m/z): 329 (M~~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.14 (2H, s), 6.79 (2H, d, J=9Hz), 7.36 (2I-I, d, J=9Hz), 7.40 (2H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.84 (2H, s) In 'the same manner as in Example 10, the following compound was obtained.
NOZ
N~1-N
~I , 4-[N-(4-iodobenzyl)-N-(4-nitrophenyl)amino~~4H-1,2,4-triazole Starting Compaunds: 4-[(4-nitrophenyl)]amino-4H-1,2,4-triazole and'p-iodobenzyl chloride 2~.:~~'~"~3 Elementary Analysis (for C15H1zINsOz) H (~) N (~) I (~) .
Calculated: 42.77 2.87 16.63 30.13 Measured: 42.68 3.01 16.46 30.26 Mass Spectrometry (m/z): 422 (M++1) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.10 (2H, s), 6.78 (2H, d, J=9Hz), 7.14 (2H, d, J=9Hz), 7.70 (2H, d, J=9Hz), 8.19 (2H, d, J=9Hz), 8.84 (2H, s) EXAMPbE 20 Tn the same manner as in Example 10, the following compound was obtained.
NOZ
N~_ N
2-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-yl)amino]methyl]quinoline Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 2-(chloromethyl)quinoline ~~.~.~"l'~3 Elementary .Analysis (for C18H14N6Oz) C ($) H (~) N (~) Calculated: 62.42 4.07 24.26 Measured: 62.42 4.22 24.30 Mass Spectrometry (m/z): 347 (M~~+1) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.52 (2H, s), 6.70 (2H, d, J=8Hz), 7.61 (1H, t, J=6Hz), 7.67 (1H, d, J=7Hz), 7.76 (1H, t, J=6Hz), 7.98-8.03 (2H, m), 8.42 (1H, d, J=7Hz), 9.08 (2H, s) In the same manner as in Example 10, the following compound was obtained.
4-[N-(4-nitrophenyl)-N-(4-pyridylmethyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-picplyl chloride Elementary Analysis (for C14H1zNsOz) C ($) H ($) N ($) Calculated: 56.75 4.08 28.36 Measured: 56.67 4.23 28.36 Mass Spectrometry (m/z ) : 297 (M+-i-1 ) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 5.23 (2H, s), 6.72 (2H, d, J=9Hz), 7.40 (2H, d, J=6Hz), 8.19 (2H, d, J=9Hz), 8.55 (2H, d, J=6Hz), 8.97 (2H, s) In the same manner as in Example 10, the following compound was obtained.
CN
N~r N
~NOz 4-[N-(4-cyanophenyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-nitrobenzyl bromide ~:~1~"~'~l3 Elementary Analysis ( for C16H1zN60z ) C (~) H (~) N (~) Calculated: 60.00 3.78 26.24 Measured: 59.75 3.71 26.28 Mass Spectrometry (m/z): 320 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 5.27 (2H, s), 6.74 (2H, d, J=9Hz), 7.65 (2H, d, J=9Hz), 7.77 (2H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.90 (2H, s) In the same manner as in Example 10, the following compound was obtained.
NOZ
IV~_ N
CN
4-[N-(4-cyanobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-cyanobenzyl bromide Elementary Analysis (for Cl6HizNsOz) C (~) H (~) N (~) Calculated: 60.00 3.78 26.24 Measured: 59.94 3.98 26.21 Mass Spectrometry (m/z): 320 (M+, ET) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
intexnal standard) &: 5.27 (2H, s), 6.76 (2H, d, J=9Hz), 7.57 (2H, d, J=9Hz), 7.84 (2H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.91 (2H, s) In the same manner as in Example 10, the following compound was obtained.
NOz N~_ N

4-[N-(4-nitrophenyl)-N-[4-(trifluoromethyl)benzyl]-amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-(trifluoromethyl)benzyl bromide Elementary Analysis (for Cl6HizFsNsOz) C (~S) H (~) N (~) F (~) Calculated: 52.90 3.33 19.28 15.69' Measured: 52.88 3.36 19.38 15.60 Mass Spectrometry (m/z): 363 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) s: 5.27 (2H, s), 6.78 (2H, d, J=7Hz), 7.59 (2H, d, J=8Hz), 7.72 (2H, d, J=8Hz), 8.21 (2H, d, J=7Hz), 8.91 (2H, s) In the same manner as in Example 10, the following compound was obtained.
NOz ~N
N~ N_ ~NOz 1-[N-(4-nitrobenzyl)-N-(4-nitrophenyl)amino]-1H-1, 2, 4-triazole Starting Compounds: 1-[(4-nitrophenyl)amino]-1H-1,2,4-triazole and p-nx.trobenzyl bromide -, ~ ~ ~. ~ '~~ '~ 3 Elementary Analysis ( for C15H1zN60a ) C ($) H ($) N (~) Calculated: 52.94 3.55 24.70 -Measured: 52.66 3.74 24.62 Mass Spectrometry (m/z): 340 (M~) Nuclear Magnetic I;esonance Spectrum ( DMSO-db, TMS
internal standard) 8: 5.33 (2H, s), 6.75 (2I-I, d, J=9Hz), 7.72 (2H, d, J=9Hz), 8.10-8.27 (5H, m), 8.84 (1H, s) Tn the same manner as in Example 10, the following compound was obtained.
~NOz N ~YN_ Br 1-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[(4-nitrophenyl)amino]-1H-1,2,4-triazole and p-bromobenzyl bromide 1:~. ~ '~ '~ 3 Elementary Analysis (for ClSHizBrN502) C (~) H (~) N (~) Br (~) Calculated: 48.15 3.23 18.72 21.35 Measured: 48.00 3.31 18.72 21.42 Mass Spectrometry (m/z): 374 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.10 (2H, s), 6.76 (2H, d, J=9Hz), 7.33 (2H, d, J=9Hz), 7.54 (2H, d, J=9Hz), 8.17 (2H, d, J=9Hz), 8.20 (1H, s), 8.72 (1H, s) In the same manner as in Example 10, the following compound was obtained.
GN
N~ N_ NOZ
1-[N-(4-cyanophenyl)-N-(4-nitrobenzyl)amino]--1H-1,2,4-triazole Starting Compounds: 1-[(4-cyanophenyl)amino]-1H-1,2,4-triazole and p-nitrobenzyl bromide _.,.
Elementary Analysis (for C16H1zNs~z) C (~) H (~) N
Calculated: 60.00 3.78 26.24 Measured: 60.02 3.91 26.21 Mass Spectrometry (m/z): 320 (M+) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 8: 5.04 (2H, s), 6.67 (2H, d, J=9Hz), 7.54 (2H, d, J=9Hz), 7.58 (2H, d, J=9Hz), 7.96 {1H, s), 8.05 (1H, s), 8.21 (2H, d, J=9Hz) In the same manner as in Example 2, the following compound was obtained.
N~z ~N
NyN-~NO
z 1-[Bis-(4-nitrophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[(4-nitrophenyl)amino]-1H-1,2,4-triazole and p-nitrofluorobenzene Elementary Analysis ( for C14H~ON604 ) C (~) H (~) N (~S) Calculated: 51.54 3.09 25.76 Measured: 51.39 3.43 25.36 Mass Spectrometry (m/z): 326 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS internal standard) s: 7.22 (4H, d, J=9Hz), 8.28 (4H, d, J=9Hz), 8.37 (1H, s), 9.24 (1H, s) NOZ
N N-N~ i 2.8 Milliliters of acetic anhydride was added to l5 ml of a pyridine solution containing 0.62 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole at room temperature and the mixture was stirred for about 2 hours. After completion,of reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogencarbonate solution was added to the residue obtained, which was then extracted several times each with ethyl acetate.
The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give 0.52 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-~:~~~~~'~3 1,2,4-triazole from the chloroform/methanol (100/1) eluate.
Mass Spectrometry (m/z): 247 (M~") Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 6: 2.13 (3H, s), 7.49 (2H, d, J=9Hz), 8.28 (2I3, d, J=9Hz), 8.52 (2H, s) ~2 N N-A proper amount of 10~ palladium-carbon was added to 15 ml of a methanol solution containing 0.38 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and the mixture was subjected to catalytic reduction in the presence of hydrogen gas at room 'temperature for about 40 minutes. After completion of reaction, the catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The .residue was purified by silica gel column chromatography to give 0.33 g of 4-(N-acetyl-N-(4-aminophenyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Mass Spectrametry (m/z): 217 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 1.97 (3H, s), 5.53 (2H, br), 6.58 (2H, d, J=9Hz), 7.35 (2H, d, J=9Hz), 8.88 (2H, s) REFERENTII1T; EXAMPLE 8 One Milliliter of a 47~ hydrobromic acid solution containing 0.32 g of 4-[N-acetyl-N-(4-aminophenyl)amino]-4H-1,2,4-triazole was cooled to 0 to 5°C, and 1 ml of an aqueous solution containing 0.1 g of sodium nitrite was gradually dropwise added 'thereto. The mixture was stirred fox about 20 minutes at the same temperature. Subsequently, this was poured into a previously prepared cold aqueous solution containing 0.55 g of cuprous bromide and 1 ml of 47~ hydrobromic acid and the mixture was stirred for about 20 hours at room temperature. The reaction mixture was neutralized with an aqueous sodium hydrogencarbonate solution and then extracted several times each with ethyl acetate. The ethyl acetate layer obtained was washed with water and W
dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give crude crystals, which were washed with ether to give 0.29 g of 4-[N-acetyl-N-(bromophenyl)amino)]-4H-1,2,4-triazole.
Mass Spectrometry (m/z): 281 (M~") Nuclear Magnetic Resonance Spectrum (DMSO-db, 'PMS
internal standard) 2.00 (3H, s), 7.74 (4H, m), 9.06 (2H, s) N~ -N ~ Br H
Milliliters of 4N hydrochloric acid was added to 0.22 g of 4-[N-acetyl-N-(4-bromophenyl)amino]-4H-1,2,4-triazole and the mixture was heated at 90°C for a'bou't 40 minutes. After cooled, 'the solution was neutralized with an aqueous sodium hydrogen carbonate solution and then extracted several times each with ethyl acetate. The ethyl acetate layer obtained was washed with water_ and dried over anhydrous magnesium sulfate, and 'the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.18 g of 4-(4-bromophenyl)amino)-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Mass Spectrometry (m/z): 239 (M+) _ 65 ~I~~'l'~3 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 80 6.45 (2H, d, J=9Hz), 7.41 (2H, d, J=9Hz), 8.77 (2H, s), 9.62 (1H, s) REFERENTIAL Ex1-1MPLE 10 N~
O
N~N--NH__~eyi~/
N'/
26.70 Grams of potassium tert-butoxide was dissolved in 100 m1 of anhydrous dimethylsulfoxide and 20.00 g of 4-amino-4H-1,2,4-triazole was added thereto, followed by stirring for 2 hours at room temperature.
Next, 50 ml of an anhydrous dimethylsulfoxide solution containing 11.00 g of 5-fluorobenzofurazane was added dropwise to the solution aver a period of 20 minutes and then the mixture was stirred fox 15 minutes. The reaction mixture was poured into 500 m1 of water and 500 g of ice and then washed with 200 ml of ethyl acetate.
The solution was 'then adjusted to have pH of 7.0 with 1 N
hydrochloric acid to give crystals. The crystals were collected by filtration, and the remaining mother liquid was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.

The solvent was removed by distillation under reduced pressure, and the crude crystals thus obtained were recrystallized from ethanol. These were combined with the previously obtained crystals to give 12.49 g of 5-[(4H-1,2,4-triazol-4-yl)amino]benzofurazane.
Mass Spectrometry (m/z): 202 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 6.09 (1H, dd, J=2Hz, 1Hz), 7.29 (1H, dd, J=lOHz, 2Hz), 8.17 (1H, dd, J=lOHz, 1Hz), 8.89 (2H, s), 10.46 (1H, brs) NC
N
~N-NH
N~
6.67 Grams of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, and 5.0U g of 4-amino-4H-1,2,4-triazole was added thereto and the mixture was stirred for 15 minutes at room temperature. Subsequently, 9 ml of an anhydrous dimethylsulfoxide solution containing 3.23 g of 2-fluorobenzonitrile was added dropwise to the solution over a period of 10 minutes, and the mixture was stirred for further_ 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and the solution was then adjusted to have pH of 5.7 with 1 N hydrochloric acid. The crystals precipitated out were collected by filtration and dried to give 2.64 g of 4-[(2-cyano-phenyl)amino]-4H-1,2,4-triazole.
Mass Spectrometry (m/z): 185 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 6.22 (1H, d, J=8Hz), 7.05 (1H, m), 7.54 (1H, m), 7.74 (1H, dd, J=8Hz, 1Hz), 8.81 (2H, s), 10.14 (1H, s) CN
N~
N-N
N~ ~0 0.56 Gram of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole was added little by little to a suspension of 0.12 g of sodium hydride in 6 ml of N,N-dimethylforxnamide at room temperature. After completion of the addition, the reaction mixture was stirred for 30 minutes at 50°C
and then cooled. With cooling, 0.42 g of 5-fluoro-benzofrazan was added thereto and then the mixture was stirred for one hour at 100°C. The solvent was removed by distillation under reduced pressure, and water was added to the resulting residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (200/1) eluate. The crude crystals were recrystallized from ethyl acetate to give 0.17 g of 5-[N-(4-cyanophenyl)-N-(4H-1,2,4-triazol-4-yl)amino]benzofrazane.
Elementary Analysis (for C15H9N~0) C (~) H (~) N (~) Calculated: 59.40 2.99 32.33 Measured: 59.43 3.0~. 32.38 Nuclear Magnotic Resonance Spectrum (CDC13, TMS
internal standard) 8: 7.06-7.27 (4H, m), 7.74 (2H, d, J=9Hz), 7.93 (1H, d, J=9Hz), 8.49 (2H, s) In 'the same manner as in Example 29, the following compound was obtained.

2~Li~'~~~3 NO z N~
N-N N
N~
\\~~ NO
a 4-(N-(4-nitrophenyl)-N-(5-nitropyridin-2-yl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 2-bromo-5-nitropyridine Elementary Analysis ( for C13H9N~O4 ) C ($) H (~) N
Calculated: 47.71 2.77 29.96 Measured: 47.46 2.90 30.04 Mass Spectrometry (m/z): 327 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 6.77 (lI-I, d, J=9Hz), 7.74 (2H, d, J=9Hz), 8.38 (2FI, d, J=9Hz), 8.53 (1H, d, J=9Hz), 9.13 (1H, s), 9.25 (2H, s) ~~1.~~~~

CN
N~
N-N
N~
F
40 Milliliters of acetonitrile was added to 500 mg of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole, 0.42 ml of 4-fluorobenzyl bromide and 746 mg of potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the resulting residue, which was then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and 'the solvent was removed by distillation. The residue was subjected to silica gel column chromatography to give crude crystals from the chloroform/methanol (100/2) eluate. The crude crystals were recrystallized from ethyl acetate to give 314 mg of 4-[N-(4-cyanophenyl)-N-(4-fluorobenzyl)amino]-4H-1,2,4-triazole.

- ~ ~. I. ~ 'l '~ 3 Elementary Analysis ( For Cl6HizNsF ) C ('k) H (~) N (~) F
Calculated: 65.52 4.12 23.88 6.48 Measured: 65.53 4.16 23.93 6.43 Mass Spectrometry (m/z): 293 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.05 (2H, s), 6.77 (2H, d, J=9Hz), 7.04-7.44 (4H, m), 7.76 (2H, d, J=9Hz), 8.78 (2I3, s) EXAMPbE 32 In the same manner as in Example 31, the following compound was obtained.
CN
N~
N--N
N~
'~''~ C1 4-[N-(4-chlorobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-chlorobenzyl bromide ~~1~"l'~3 Elementary Analysis ( for C16H1zN5Cl ) C (~) H (~) N (~) Cl Calculated: 62.04 3.90 22.61 11.45 Measured: 61.97 4.10 22.59 11.26 Mass Spectrometry (m/z): 309 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.07 (2H, s), 6.75 (2H, d, J=9Hz), 7.37 (4H, s), 7.?6 (2H, d, J=9Hz), 8.80 (2H, s) Tn the same manner as in Example 31, the following compound was obtained.
CN
N~
N-N
N-=-~
~I
4-[N-(4-cyanophenyl)-N-(4-iodobenzyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-.iodobenzyl chloride ~~16"I "l3 Elementary Analysis ( for Ci6H12N5I
C (~) H ($) N (~) I
Calculated: 47.90 3.01 17.46 31.63 Measured: 47.76 3,05 17.46 31.51 Mass Spectrometry (m/z): 401 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-dfi, TMS
internal standard) 6: 5.03 (2H, s), 6.74 (2H, d, J=9Hz), 7.13 (2H, d, J=8Hz), 7.68 (2H, d, J=8Hz), 7.76 (2H, d, J=9Hz), 8.81 (2H, s) In the same manner as in Example 31, the following compound was obtained.
CN
N~
N-N
N~
~ CF3 4-[N-(4-cyanophenyl)-N-[(4-trifluoromethyl)benzyl]-amino]-4I-I-1, 2, 4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino)~4H-1,2,4-triazole and 4-(trifluoromethyl)benzyl bromide - 74 _ ~. :l ~ '~~ '~ 3 Elementary Analysis (for C1~H12NSF3) C (~) H (~) N (~) F (~) Calculated: 59.48 3.52 20.40 16.60 Measured: 59.40 3.59 20.41 16.48 Mass Spectrometry (m/z): 343 (M+) Nuclear Magnetic Resonance Spectrum (nMSO-db, TMS
internal standard) 8: 5.20 (2H, s), 6.75 (2H, d, J=9Hz), 7.58 (2H, d, J=8Hz), 7.71 (2H, d, J=8Hz), 7.77 (2H, d, J=9Hz), 8.88 (2H, s) Tn the same manner as in Example 31, the following compound was obtained.
NOz N~
N-N
N~
rz 4-[N-[(5-chlorothiophen-2-yl)methyl]-N-(4-nitro-phenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 2-chloro-5-(chloromethyl)-thiophene Elementary Analysis ( f'or Cl3HioNsClOzS ) ) H (~) N (~) c1 (~) s (~) Calculated: 46.50 3.00 20.86 10.56 9.55 Measured: 46.30 3.02 20.78 10.69 9.48 Mass Spectrometry (m/z): 335 (Me) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.30 (2H, s), 6.74-7.02 (4H, m), 8.20 (2H, d, J=lOHz), 8.81 (2H, s) ExAMPLE 36 In the same manner as in Example 31, the following compound was obtained.
NO z N~
N-N
N
4-[N-(4-nitrophenyl)-N-(thienylmethyl)amino]-4H-1, 2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole arid 2-(chloromethyl)thiophene Elementary Analysis ( for C13H11NSOzS ) C ($) H (~) N (~) S
Calculated: 51.82 3.68 23.24 10.64 Measured: 51.94 3.72 23.10 10.60 ~. :~ ~ '~ '~ 3 Mass Spectrometry (m/z): 301 (M'") Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.35 (2H, s), 6.80-7.02 (4H, m), 7.54 (1H, d, J=5Hz), 8.20 (2H, d, J=lOHz), 8.74 (2H, s) ExAMPLE 37 Tn the same manner as in Example 31, the following compound was obtained.
Br N~
N --- N
N~ ' RCN
4-[N-(4-bromophenyl)-N-(4-cyanobenzyl)amino]-4H-1, 2, 4-triazole Starting Compounds: 4-[(4-bromophenyl)amino]-4H-1,2,4-triazole and oc-bromo-p-tolunitrile Elementary Analysis (for Cz6H~zIVsBr) C (~) H (q~) N (~k) Br (~) Calculated: 54.26 3.41 19.77 22.56 Measured: 54.17 3.55 19.70 22.43 Mass Spectrometry (m/z): 354 (M~") ~1~.~'l"l~
Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.07 (2H, s), 6.66 (2H, d, J=lOHz), 7.45-7.90 (6H, m), 8.84 (2H, s) In the same manner as in Example 31, the following compound was obtained.
Br N~
N - N
N~
~NOZ
4-[N-(4-bromophenyl)-N-(4-nitrobenzyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-bromophenyl)amino]-4H-1,2,4-triazole and 4-nitrobenzyl bromide Elemewtary Analysis ( for ClSHizNsOzBr ) C (~) H (~S) N (~) Br (~) Calculated: 48.15 3.23 18.72 21.35 Measured: 48.08 3.39 18.66 21.19 Mass Spectrometry (m/z): 374 (M*) _ 78 -~~.~6~'~3 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.13 (2I-I, s), 6.68 (2H, d, J=9Hz), 7.51 (2H, d, J=9Hz), 7.65 (2H, d, J=9Hz), 8.19 (2H, d, J=9Hz), 8.88 (2H, s) In the same manner as in Example 31, the following compound was obtained.
CN
N~ ii~~
N-N
N~
4-[N-benzyl-N-{4-cyanophenyl)amino]-4I-I-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H--1,2,4-triazole and benzyl bromide Elementary Analysis (for C16H~~N5) C (~) H (Rs) N (~) Calculated: 69.80 4.76 25.44 Measured: 69.66 4.84 25.43 Mass Spectrometry (m/z): 275 (M+) Nuclear Magnetic Resonance Spectrum (DriSO-db, TMS
internal standard) 8: 5.07 (2H, s), 6.76 (2H, d, J=9Hz), 7.32 (5H, _ 79 _ ~:~I~"~'~3 s), 7.76 (2H, d, J=9Hz), 8.80 (2H, s) In the same manner as in Example 31, the following compound was obtained.
NOa N~
N-N
N~
4-[N-benzyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrobenzyl)amino]-4H-1,2,4-triazole and benzyl bromide Elementary .Analysis (for C1gH13N5p2) C (~) H (~) N (~) Calculated: 61.01 4.44 23.72 Measured: 60.68 4.49 25.67 Mass Spectrometry (m/z): 295 (M*) Nuclear Magnetic Resonance Spectrum (DMSn-db, TMS
internal standard) 8: 5.13 (2I-I, s), 6.79 (2H, d, J=9Hz), 7.33 (5H, s), 8.20 (2H, d, J=9Hz), 8.83 (2H, s) In the same manner as in Example 31, the following compound was obtained.

CN
N~
N-N
N~
~O
N' 5-[[N-(4-cyanophenyl.)-N-(4H-1,2,4-triazol-4--yl)amino]methyl]benzofurazan Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 5-bromomethylbenzofurazan Elementary Analysis (for Cz6H11N~0) C (~) H (~) N (~S) Calculated: 60.56 3.49 30.90 Measured: 60.56 3.41 31.05 Mass Spectrometry (m/z): 317 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 5.27 (2H, s), 6.75 (2H, d, J=9Hz), 7.61 (1H, d, J=9Hz), 7.78 (2H, d, J=9Hz), 8.02 (1H, s), 8.08 (1H, d, J=9Hz), 8.99 (2H, s) In the same manner as in Example 31, the following compound was obtained.
NOZ
N~
N--N
N~
~O
N' ~ 1. :~ i~'~l r~ 3 5-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-yl)amino]methyl]benzofurazan Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 5-bromomethylbenzofurazan Elementary Analysis (for CISHiiNy3) C (~) H (~) N (~) Calculated: 53.41 3.29 29.07 Measured: 53.27 3.38 29.08 Mass Spectrometry (m/z): 337 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.33 (2H, s), 6.78 (2H, d, J=7Hz), 7.61 (1H, d, J=9Hz), 8.04 (1H, s), 8.09 (1H, d, J=9Hz), 8.21 (2I3, d, J=7Hz), 9.03 (2H, s) In the same manner as in Example 31, the following compound was obtained.
CN
N~
N - N

'~ C1 4-[N-(4-cyanophenyl)-N-(3,4-dichlorobenzyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 3,4-dichlorobenzyl chloride Elementary Analysis (for Cl6HiiC1zN5) C (~) H (~) N (~) C1 (~) Calculated: 55.83 3.22 20.35 20.60 Measured: 55.98 3.2? 20.48 20.46 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.09 (2H, s), 6.74 (2H, d, J=9Hz), 7.31 (2H, dd, J=9Hz, J=2Hz), 7.60 (1H, d, J=9Hz), 7.63 (1H, d, J=2Hz), 7.77 (2H, d, J=9Hz), 8.86 (2H, s) In the same manner as in Example 31, 'the following compound was obtained..
CN
N~
N-N
N~

~NOz 4-[N-(4-cyanophenyl)-N-[1-(4-nitrophenyl)ethyl]-amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-(1-iodoethyl)nitrobenzene Elementary .Analysis (for C1~H14Ns0z) C (~) H (~) N
Calculated: 61.07 4.22 25.14 Measured: 60.92 4.27 25.11 Mass Spectrometry (m/z): 334 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 1.48 (3H, d, J=7Hz), 5.88 (1H, q, J=7Hz), 6.66 (2H, d, J=9Hz), ?.68 (2H, d, J=9Hz), 7.74 (2H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.77 (2H, s) In the same manner as in Example 31, the following compound was obtained.
CN
N=~
N -' N
N~
~NOz 4-[[N-(4-cyanophenyl)-N-[2-(4-nitrophenyl)ethyl]-amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-nitrophenethyl bromide Elementary Analysis (for C1~H1,,N60z) C (~) H (~) N (~) Calculated: 61.07 4.22 25.14 Measured: 61.01 4.26 25.14 Mass Spectrometry (m/z): 334 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 2.99 (2H, 't, J=7Hz), 4.18 (2H, t, J=7Hz), 6.26 (2H, d, J=9Hz), 7.61 (2H, d, J=9Hz), 7.72 (2H, d, J=9Hz), $.17 (2H, d, J=9Hz), 8.88 (2H, s) EXAMPhE 46 In the same manner as in Example 31, the following compound was obtained.
CN
N~
N - N
N~
~r~
4-[N-(2-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 2-bromobenzyl bromide F ~~
Elementary .Analysis {for C16I3izBrNS) C (~) H (~) N (~) Br Calculated: 54.26 3.41 19.77 22.56 Measured: 54.10 3.32 19.85 22.72 Mass Spectrometry (m/z): 353 {M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, 'PMS
internal standard) s: 5.14 (2H, s), 6.75 (2H, d, J=9Hz), 7.27-7.36 (3H, m), 7.65 {1H, d, J=7Hz), 7.78 (2H, d, J=9Hz), 8.80 (2H, s) Tn the same manner as in Example 31, the following compound was obtained.
CN
N~
N-N
Br 4-[N-(3-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole Starting Compaunds: 4-[(cyanophenyl)amino]-4H- a 1,2,4-triazole and 3-bromobenzyl bromide Elementary Analysis (for C16H1zBrN5) C (~) H (~) N (~) Br (~) Calculated: 54.26 3.41 19.77 22.56 Measured: 54.16 3.29 19.89 22.59 Mass Spectrometry (m/z): 353 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.09 (2H, s), 6.75 (2H, d, J=9Hz), 7.27-7.34 (2H, m), 7.50 (1H, d, J=7Hz), 7.56 (1H, s), 7.77 (2H, d, J=9Hz), 8.86 (2H, s) In the same manner as in Example 31, the following compound was obtained.
~O
N~
LI -- N
N~
~ NOZ
5-[N-(4-nitrobenzyl)-N-(4H-1,2,4-triazol-4-yl)amino]benzofurazan Starting Compounds: 5-[(4H-1,2,4-triazol-4-yl)aminojbenzofurazan and 4-nitrobenzyl bromide _ 87 _ W
Elementary Analysis (for CISHlNy3) C (~) H ($) N (~) Calculated: 53.41 3.29 29.07 Measured: 53.13 3.28 29.10 Mass Spectrometry (m/z): 337 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.29 (2H, s), 7.04 (1H, dd, J=lOHz, 2Hz), 7.15 (1H, d, J=2Hz), 7.69 (2H, d, J=9Hz), 8.05 (1H, d, J=lOHz), 8.21 (2H, d, J=9Hz), 8.92 (2H, s) In the same manner as in Example 31, the following compound was obtained.
~0 N~ ~~~~~~' N - N
N~ [
Br 5-[N-(4-bromobenzyl)-N-(4H-1,2,4-triazol-4-yl)amino]benzofurazan Starting Compounds: 5-[(4H-1,2,4-triazol-4-yl)amino)benzafurazan and 4-bromobenzyl bromide Elementary Analysis (for Cz5H11BrN60) C (~) H ($) N (~) Br Calculated: 48.54 2.99 22.64 21.53 Measured: 48.36 3.03 22.71 21.67 Mass Spectrometry (m/zj: 370 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.07 (2H, s), 7.02 (1H, dd, J=lOHz, 2Hz), 7.18 (1H, d, J=2Hz), 7.31 (2H, d, J=8Hz), 7.54 (2H, d, J=8Hz), 8.03 (1H, d, J=lOHz), 8.83 (2H, s) In the same manner as in Example 31, the following compound was obtained.
NC
N~
N - N
N~
'~ Br 4-[N-(4-bromobenzyl)-N-(2-cyanophenyl)amino]-4H-1, 2, 4-triazole Starting Compounds: 4-[(2-cyanophenyl)amino]-4H-1,2,4-triazole and 4-bromobenzyl bromide - 89 _ ~~.~G~~~3 Elementary Analysis ( for C16Hi2N5Br ) C ($) H (~) N (~) Br Calculated: 54.26 3.41 19.77 22.56 Measured: 54.19 3.41 19.90 22.42 Mass Spectrometry (m/z): 355 (M~) Nuclear Magnetic Resonance Spectrum (pMSO-db, TMS
internal standard) 6: 4.92 (2H, s), 7.37 (2H, d, J=9Hz), 7.40-7.53 (2H, m), 7.54 (2H, d, J=9Hz), 7.75-7.79 (1H, m), 7.89 (1H, d, J=8Hz), 8.86 (2H, s) In the same manner as in Example 31, the following compound was obtained.
NOZ
N
N --- N
N~
Br 4-[[N-(4-bromonaphthalen-1-yl)methyl]-N-(4-nitro-phenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and cx,4-dibromo-1-methylnaphthalene Elementary Analysis (for C19H14NSBrOz) C (~) H (~) N (~) Br (~) Calculated: 53.79 3.33 16.51 18.83 Measured: 53.77 3.38 16.46 18.87 Mass Spectrometry (m/z): 425 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.61 (2H, s), 6.90 (2H, d, J~9Hz), 7.35 (1H, d, J=8Hz) 7.68-7.83 (3H, m), 8.09-8.29 (4H, m), 8.64 (2H, s) In the same manner as in Example 31, the following compound was obtained.
CN
W
NyN - N
Br 1-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazale Starting Compounds: 1-[(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-bromobenzyl bromide Physicochemical Properties:
Elementary Analysis (for C16H1zNsBr) C (~) H ($) N (~) Br (~) Calculated: 54.26 3.41 19.77 22.56 Measured: 54.30 3.43 19.84 22.75 Mass Spectrometry (m!z): 353 (M+-1) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 6: 4.87 (2H, s), 6.69 (2H, d, J=9Hz), 7.14 (2H, d, J=9Hz), 7.47 (2H, d, J=9Hz), 7.57 (2H, d, , J=9Hz), 7.87 (1H, s), 8.03 (1H, s) N~ ~ ~ ~ CF3 3.36 Grams of potassium tert-butoxide was added to 15 ml of anhydrous dimethylsulfoxide and the mixture was stirred for 30 minutes at room temperature. Next, 2.52 g of 4-amino-4H-1,2,4-triazole was added -to the solution. After the reaction mixture was stirred for 15 minutes at room temperature, 1.64 g of 4-fluorobenzo-trifluoride was added thereto and the mixture was stirred for further 30 minutes at room temperature. Ice-water was added to the reaction mixture, which was then ~~.~.~~~rl ~
neutralized with a diluted hydrochloric acid. The crystals as precipitated out were collected by filtration to give 1.93 g of 4-[(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 6.62 (2H, d, J=8Hz), 7.60 (2H, d, J=8Hz), 8.82 (2H, s), 10.06 (1H, br) N~
N~ ~ N
'~.~''~Hr 0.23 Gram of 4-[(4-trifluoromethylphenyl)-amino]-4H-1,2,4-triazole, 0.28 g of 4-bromobenzyl bromide and 0.17 g of anhydrous potassium carbonate were added to ml of acetonitrile and the mixture was stirred for 3 hours at room temperature. The solvent was removed by distillation and water was added to the residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give crude crystals ~~.~~r~~13 from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate/ether to give 0.22 g of 4-[N-(4-bromobenzyl)-N-(4-trifluoromethylphenyl)amino]-4I-I-1,2,4-triazole.
Elementary Analysis {for Cz6HlzN,~BrF3) H (~) N (~) Br (~) F (~) Calculated: 48.38 3.05 14.11 20.12 14.35 Measured: 48.46 3.04 14.06 20.36 14.12 Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) E: 4.86 (2H, s), 6.74 (2H, d, J=9Hz), 7.13 (2H, d, J=9Hz), 7.49 (2H, d, J=9Hz), 7.57 (2H, d, J=9Hz), 8.22 (2H, s) Tn the same manner as in Example 53, the following compounds were obtained.

CN
N~
N~ !' N
~C02 Me 4-[N-(4-cyanophenyT)-N-(4-methoxycarbonylbenzyl)-amino]-4H-:1,2,4-triazole Starting Compounds: 4-[N-(4-cyanophenyl)amino]-4H--1,2,4-triazole and methyl 4-bromomethylbenzoate r!
Elementary Analysis (for C18H15NSOz) C (~S) H (~) N(~) Calculated: 64.86 4.54 21.01 Measured: 64.77 4.54 21.07 Mass Spectrometry (m/z): 333 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 3,84 (3H, s), 5.18 (2H, s), 6.74 (2H, d, J=9Hz), 7.49 (2H, d, J=9Hz), 7.76 (2H, d, J=9Hz), 7.91 (2H, d, J=9Hz), 8.84 (2H, s) N~
N~ r N.
1'~~C02 Me 4-[N-(4-methoxycarbonylbenzyl)-N-(4-nitrophenyl)-amino]-4H-1,2,4-triazole Starting Compounds: 4-(N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromomethylbenzoate Elementary Analysis ( fox C1~H~5NSO4 ) C ($) H (~) N (~) Calculated: 57.79 4.28 19.82 Measured: 57.60 4.26 19.86 Mass Spectrometry (m/z): 353 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 3.85 (3H, s), 5.25 (2H, s), 6.79 (2H, d, J=9Hz), 7.51 (2H, d, J=8Hz), 7.93 (2H, d, J=8Hz), 8,20 (2H, d, J=9Hz), 8.88 (2H, s) N~ _ ~CH3 N~ N.
N
N' 1-Methyl-6-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-yl)amino]methyl]-1H-benzotriazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 6-chloromethyl-1-methyl-1H-benzo-triazole Elementary .Analysis (for ClsHlr~NaOz) C ($) H (~) N (~) Calculated: 54.85 4.03 31.98 Measured: 54.83 4.05 32.21 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 4.28 (3H, s), 5.34 (2H, s), 6.82 (2H, d, J=9Hz), 7.37 (2H, dd, J=9Hz, 2Hz), 7.84 (1H, d, J=2Hz), 8.00 (2H, d, J=9Hz), 8.21 (2H, d, J=9Hz), 8.91 (2H, s) NOZ
N~ .' N~ .~ N
N
~N - CHg 2-Methyl-5-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-yl)amino]methyl]-2H-benzotriazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 5-chloromethyl-2-methyl-2H-benzo-triazole Elementary Analysis (for C16Hi4Na0a) C (~) H (~) N ( Calculated: 54.85 4.03 31.98 Measured: 54.68 4.02 32.08 Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 4.74 (3H, s), 5.28 (2H, s), 6.84 (2H, d, J=9Hz), 7.42 (2H, dd, J=9Hz, 2I-Iz), 7.84 (1H, d, J=2Hz), 7.89 (2H, d, J=9Hz), 8.21 (2H, d, J=9Hz), 8.84 (2H, s) ~ 1 ~. 6'~'~ 3 N~
N~ N
~~N
N' I

1-Methyl-5-([N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-y1)amino]methyl.]-1H-benzotriazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 5-chloromethyl-1-methyl-1H-benzo-triazole Elementary Analysis ( for C16Hi4Ns0a ) C ($) H (~) N (~) Calculated: 54.85 4.03 31.98 Measured: 54.77 4.05 32.08 Nuclear Magnetic Resonance Spectrum (DM50-db, TMS
internal standard) 8: 4.30 (3H, s), 5.30 (2H, s), 6.85 (2H, d, J=9Hz), 7.54 (2H, dd, J=9Hz, 2Hz), 7.84 (2H, d, J=9Hz), 7.98 (1H, d, J=2Hz), 8.21 (2H, d, J=9Hz), 8.84 (2H, s) NOZ
N°~
N- N
N~
6-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazol-4-y1)amino]methyl.]benzothiazole Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 6-(chloromethyl)benzothiazole Mass Spectrometry (m/z): 352 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.31 (2H, s), 6.81 (2H, d, J=9Hz), 7.52 (1H, dd, J=9Hz, J=2Hz), 8.06 (1H, d, J=9Hz), 8.17 (1H, d, J=2Hz), 8.21 (2H, d, J=9Hz), 8.89 (2H, s), 9.40 (1H, s) EX.bIMPLE 6 0 N~
~~N--N
Br 4-[N-[(2-bromothiazol-5-yl)methyl]-N-(4-nitro-phenyl)amino]-4H-1,2,4-triazole _ 99 -Starting Compounds: 4-(4-nitrophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole Elementary Analysis ( for CIZH~N60zBrS ) C (~) H (~) N (~) S (~) Br Calculated: 37.81 2.38 22.05 8.41 20.96 Measured: 37.64 2.35 21.96 8.29 20.71 Mass Spectrometry (m/z): 379 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-dfi, TMS
internal standard) 6: 5.42 (2H, s), 6.83 (2H, d, J=lOHz), 7.61 (1H, s), 8.21 (2H, d, J=lOHz), 8.88 (2H, s) CN
N~
N~ ~ N
Br 4-[N-[(2-bromothiazol-5-yl)methyl]-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole Starting Compounds: 4-(4-cyanophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole Elementary Analysis (for. C13H9N6SBr) C (~) H (~) N (~) Br (~) S (~) Calculated: 43.23 2.51 23.27 22.12 8.88 Measured: 43.08 2.41 23.27 22.27 8.75 21~.~'1~13 Mass Spectrometry (m/z): 362 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.36 (2H, s), 6.79 (2H, d, J=9Hz) 7.58 (1H, s), 7.79 (2H, d, J=9Hz), 8.84 {2H, s) NHCOCI-i3 N~
~~N-N
~ Br 0.28 Milliliter of acetic anhydride was added to ml of a pyridine solution containing 0.35 g of 4-[N-(4-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole at room temperature and 'the mixture was stirred for about minutes. After reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogen carbonate solution was added to the resulting residue, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 0.33 g of 4-[N-(4-acetyl-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Elementary Analysis (for C1~H16NSOBr) C (~) H (~) N (~) Calculated: 52.86 4.18 18.13 Measured: 52.85 4.22 18.24 Mass Spectrometry (m/z): 387 (M~+1) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 2.01 (3H, s), 4.86 (2H, s), 6.78 (2H, d, J=9.OHz), 7.27 {2H, d, J=8.6Hz), 7.51 (4H, d, J=9.OHz), 8.75 (2H, s), 9.88 (1H, br) N~
N~ - N
~NOZ
0.23 Gram of 4-[(4-trifluoromethylphenyl)-amino]-4H-1,2,4-triazole was added little by little to an N,N-dimethylformamide suspension of 0.04 g of sodium hydride at room temperature. The mixture was stirred fox 30 minutes at room temperature, and 0.15 g of 4-fluoronitrobenzene was added thereto and the mixture was stirred for 15 minutes at 100°C. The solvent was removed by distillation under reduced pressure and water was ~. :~ ~ '~ '~ 3 added to -the residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The crystals thus -obtained were recrystallized from a mixed solvent of ethyl acetate/ether to give 280 mg of 4-[N-(4-nitrobenzyl)-N-(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Elementary Analysis (for C15H10N5F3~2) C (~) H (~) N (~) F ($) Calculated: 51.58 2.89 20.05 16.32 Measured: 51.58 2.84 20.11 16.22 Nuclear Magnetic Resonance Spectru3h (CDC13, TMS
internal standard) 8: 6.90 (2H, d, J=9Hz), 7.24 (2H, d, J=8Hz), 7.72 (2I3, d, J=8Hz), 8.22 (2H, d, J=9Hz), 8.47 (2H, s) In the same manner as in Example 53, the following compounds were obtained.

CN
~N
NyN- N
~''- CN

i 1-[N-(4-cyanobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-cyanobenzyl bromide Elementary Analysis ( for Cl~HlzNs ) C ($) H (~) N (~) Calculated: 67.99 4.03 27.98 Measured: 67.94 4.17 27.99 Mass Spectrometry (m/z) : 300 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-d6, TMS
internal standard) 8: 5.18 (2H, s), 6.70 (2H, d, J=9Hz), 7.61 (2H, d, J=9Hz), 7.75 (2H, d, J=9Hz), 7.82 (2H, d, J=9Hz), 8.19 (1H, s), 8.77 (1H, s) CN
~N
NON- N
OMe 1-[N-(4-cyanophenyl)-N-(4-methoxybenzyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-methoxybenzyl chloride ~a:l~ ~'~3 Elementary Analysis (for C17H1sNs0) C (9b) H (~) N
Calculated: 66.87 4.95 22.94 Measured: 66.88 5.09 22.92 , Mass Spectrometry (m/z): 305 (M'") Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) s: 3.72 (3H, s), 4.93 (2H, s), 6.77 (2H, d, J=9Hz), 6.85 (2H, d, J=9Hz), 7.23 (2H, d, J=9Hz), 7.74 (2H, d, J=9Hz), 8.15 (1H, s), 8.53 (1H, s) CN
N~
~NN - N

1-[N-(4-chlorobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1Fi-1,2,4-triazole and 4-chlorobenzyl chloride Elementary Analysis ( for Cl6HizNsC1 ) C (~) H (g) N (~) C1 Calculated: 62.04 3.90 22.61 11.45 Measured: 61.85 3.94 22.64 11.53 Mass Spectrometry (m/z): 309 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.05 (2I3, s), 6.74 (2H, d, J=9Hz), 7.38 (4H, s), 7.75 (2H, d, J=9Hz), 8.17 (1H, s), 8.66 (1H, s) CN
N~
~NN --- N
Bra 1-[N-(2-bromobenzyl)-N-(4-cyanophenyl)amino]-1H--1, 2, 4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 2-bromobenzyl bromide Elementary Analysis (for Cl6HiaNsBr) C (~) H (~) N (~) Br Calculated: 54.25 3.41 19.77 22.56 Measured: 54.05 3.42 19.78 22.66 Mass Spectrometry (m/z): 353 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.10 (2H, s), 6.76 (2H, d, J---9Hz), 7.24-7.34 (3H, m), 7.66 (1H, dd, J=lHz, 8Hz), 7.71 '~~~.~.~"~~3 (2H, d, J=9Hz), 8.17 (1H, s), 8.56 (1H, s) CN
N~
~ N- N
N' Br 1-[N-(3-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 3-bromobenzyl bromide Elementary Analysis (for C16H12NsBr) C (~) H (~) N (~) Br ( Calculated: 54.25 3.41 19.77 22.56 Measured: 54.08 3.41 19.78 22.64 Mass Spectrometry (m/z): 353 (M~) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
intexnal standard) 8: 5.07 (2H, s), 6.72 (2H, d, J=9Hz), 7.29 (1H, t, J=8Hz), 7.38 (1H, d, J=8Hz), 7.49 (1H, d, J=8Hz), 7.61 (1H, s), 7.75 (2H, d, J=9Hz), 8.19 (1H, s), s.74 (1H, s) ..

CN
~N
N~- N
1-[N-benzyl-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and benzyl bromide Elementary Analysis (for C16H13N5) C (~) H (~) N
Calculated: 69.80 4.76 25.44 Measured: 69.72 4.81 25.41 Mass Spectrometry (m/z): 275 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 5.03 (2H, s), 6.75 (2H, d, J=9Hz), 7.28-?.36 (5H, m), 7.75 (2H, d, J=9Hz), $.:16 (1H, s), 8.62 (1H, s) CN
N~'N- N
HIV
F
1-[1~1-(4-fluorobenzyl)-Id-(4-cyanophenyl)amino]-1H-1,2,4-triazo1e Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-fluorobenzyl bromide Elementary Analysis (for Cl6HizNsF) C (~) H (~) I3 ($) F
Calculated: 65.52 4.12 23.88 6.48 Measured: 65.60 4.23 23.83 6.47 Mass Spectrometry (m/z): 293 (M'") Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) &: 5.02 (2H, s), 6.76 (2H, d, J=9Hz), 7.03-7.47 ( 4H, m) , 7 . 75 ( 2H, d, J=9FIz ) , 8 .15 ( :LH, s ) , 8.60 (1H, s) ~.1 ~ '~ ~'l 3 CN
N~'N- N
HIV
I
1-[N-(4-cyanophenyl)-N-(4-iodobenzyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-iodobenzyl chloride Elementary Analysis ( far C16H1zNsI ) C (~) H ($) N (~) I
Calculated: 47.90 3.01 17.46 31.63 Measured: 47.62 3.00 17.50 31.71 Mass Spectrometry (m/z): 401 (M*) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
iwternal standard) 8: 4.85 (2H, s), 6.69 (2H, d, J=7Hz), 7.01 (2I-I, d, J=8Hz), 7.52-7.71 (4H, m), 7.87 (1H, s), 8.02 (1H, s) . EXAMPLE 72 CN
N~T- N

~N
CHg - llo -_ ~L~.~~'~~
1-[N-(4-cyanophenyl)-N-(4-methylbenzyl)amino]-1H-1,2,4-triazole Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and oc-bromo-p-xylene Elementary Analysis (for C1~H15N5) C (~) H (~) N ( Calculated: 70.57 5.23 24.20 Measured: 70.46 5.28 24.12 Mass Spectrometry (m/z): 289 (M+) Nuclear Magnetic Resonance Spectrum (CDC13, TMS
internal standard) 6: 2.32 (3H, s), 4.85 (2H, s), 6.71 (2H, d, J=7Hz), 7.11 (4H, s), 7.56 (2H, d, J=7Hz), 7.80 (1H, s), 8.01 (1H, s) EXAMPLE '13 CN
N
~~ ., N
5-[[N-(4-cyanophenyl)-N-(1H-1,2,4-triazol-1-yl)-amino]methyl]benzofurazan Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan r~~
~~~~~~~13 Elementary Analysis (for CISHmN~O) C ($) H (~) N (~S) Calculated: 60.56 3.49 30.90 Measured: 60.51 3.53 30.88 Mass Spectrometry (m/z): 317 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.26 (2H, s), 6.75 (2H, d, J=9Hz), 7.68 (1H, d, J=9Hz), 7.77 {2H, d, J=9Hz), 8.03 (1H, s), 8.08 (1H, d, J=9Hz), 8.22 (1H, s), 8.89 (1H, s) N~
~NN- N
N
~O
. N.
5-([N-(4-n:itrophenyl)-N-(1H-1,2,4-triazol-1-yl)-amino]methyl]benzofurazan Starting Compounds: 1-[N-(4'-nitrophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan Elementary Analysis (for C15H11N7~3) C (~) H (~) N (~) Calculated: 53.41 3.29 29.07 Measured: 53.29 3.32 29.16 Mass Spectrometry (m/z): 337 (M*) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 6: 5.33 (2H, s), 6.78 (2H, d, J=9Hz), 7.70 (1H, d, J=9Hz), 8.07 (1H, s), 8.10 (1H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8.26 (1H, s), 8.95 (1H, s) EXAMPLE ?5 O
NON N
N\\
S
5-[N-(4-thiazolylmethyl)-N-(4H-1,2,4-triazol-4-yl)-amino]benzofurazan Starting Compounds: 5-[N-(4H-1,2,4-triazol-4-y1)-amino]benzofurazan and 4-chloromethylthiazole Elementary Analysis ( for CloH9N~OS ) C (~) H (~) N (~) S
Calculated: 48.15 3.03 32.76 10.71 Measured: 48.05 3.05 32.72 10.60 Mass Spectrometry (m/z): 299 (M+) Nuclear Magnetic Resonance Spectrum (DMSO-db, TMS
internal standard) 8: 5.26 (2H, s), 7.04-7.06 (2H, m), 7.75 (1H, s) 8.01 (1H, d, J=9Hz), 8.77 (2H, s), 9.11 2 ~. ~. ~ '~ '~ 3 (1H, s) Formulation of Oral Preparation:

Tablet Core Content (mg) Compound of Example 15 1.0 Lactose 76.4 Corn Starch 19.3 Hydroxypropylcellulose 3.0 Magnesium Stearate 0.3 Subtotal 100 Tablet Coat Hydroxypropyl Methylcellulose 2910 2.9 Polyethylene Glycol 6000 0.4 Titanium Dioxide 1.6 Talc 0.1 Subtotal 5 Total 105 Preparation of 1 mg-tablet:
7 Grams of the compound of Example 15 and 534.8 g of lactose were blended in a polyethylene bag. The mixture was mixed and milled in a sample mill (manufactured by Hosokawa Micron Co.). 541.8 Grams of the milled mix and 135.1 g of corn starch were uniformly blended with a fluid granulating coating device (manufactured by Ohkawara Manufacturing Co.). To 'this was sprayed 210 g of 10~ hydroxypropyl cellulose solution for granulation.
- 114 ,~

~~~~°~3 After dried, the granules formed were passed through a 20-mesh sieve, to which 2.1 g of magnesium stearate was added. These were formed into 100 mg-weight tablets with a rotary tabletting machine (manufactured by Hata Ironworks Co.) using a mortar-pounder of 6.5 mm~ x 7.8 R.
350 Grams of a coating liquid containing 20.3 g of hydroxypropyl.methylcellulose, 2.8 g of polyethylene glycol 6000, 11.2 g of titanium dioxide and 0.7 g of talc was sprayed over the tablets (100 mg/tablet) in a coating device (manufactured by Freund Industrial Co.) to form film-coated tablets each with a coat of 5 mg/tablet.

Claims (6)

WE CLAIM:

1. A triazolyl-substituted tertiary amino compound of general formula (I):
wherein A represents a single bond, a lower alkylene group or a carbonyl group;
B represents a lower alkyl group, a phenyl or naphthyl group optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an benzoyl or naphthylcarbonyl group, an benzoyloxy or naphthylcarbonyloxy group, a carbamoyl group, a mono-or di-lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group and a mono- or di-lower alkylsulfamoyl group a 5- or 6 membered heterocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an benzoyl or naphthylcarbonyl group, an benzoyloxy or naphthylcarbonyloxy group, a carbamoyl group, a mono-or di-lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group and a mono- or di-lower alkylsulfamoyl group, or a bicyclic fused heterocyclic group composed of said hetero ring and a benzene ring; D ring represents an phenyl or naphthyl group optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an benzoyl or naphthylcarbonyl group, an benzoyloxy or naphthylcarbonyloxy group, a carbamoyl group, a mono-or di-lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group and a mono- or di-lower alkylsulfamoyl group, a 5- or 6-membered heterocyclic group having from 1 to 3 hetero atoms of oxygen, sulfur and/or nitrogen atoms optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an benzoyl or naphthylcarbonyl group, an benzoyloxy or naphthylcarbonyloxy group, a carbamoyl group, a mono-or di-lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group and a mono- or di-lower alkylsulfamoyl group, or a bicyclic fused heterocyclic group composed of said hetero ring and a benzene ring optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a mono-or di-lower alkylamino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group, an benzoyl and naphthylcarbonyl group, an benzoyloxy or naphthylcarbonyloxy group, a carbamoyl group, a mono-or di-lower alkylaminocarbonyl group, a sulfonic acid group, a lower alkylsulfonyl group, a sulfamoyl group and a mono- or di-lower alkylsulfamoyl group; and E ring represents a 4H-1,2,4-triazole ring, a 1H-1,2,4-triazole ring or a 1H-1,2,3-triazole ring; or a salt thereof with the proviso that ring D is not a 4-nitrophenyl, 4-fluorophenyl or 4-chlorophenyl group when ring E is IH-1, 2, 4-triazole, A is -CH(CH3)-, and B is 2, 4-dichlorophenyl, and that ring D is not a 4-nitrophenyl group when ring E is 1H-1, 2, 4-triazole, A is -CH(CH2CH3)- and B is 2, 4-dichlorophenyl.

2. The compound or a salt thereof as claimed in claim 1, wherein the phenyl or napthyl group, heterocyclic group or bicyclic fused heterocyclic group of B or D ring is substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group and a lower alkanoylamino group.

3. The compound or a salt thereof as claimed in claim 1, wherein the phenyl or naphthyl group of B or D ring is a phenyl group substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group and a nitro group.

4. 4-[N-(4-Bromobenzyl)-N-(4-cyanophenyl)-amino]4H-1,2,4-triazole or a salt thereof.

5. 4-[N-(4-Bromobenzyl)-N-(4-nitrophenyl)-amino]4H-1,2,4-triazole or a salt thereof.

6. A pharmaceutical composition for aromatase inhibition, which comprises, as the active ingredient, a triazolyl-substituted tertiary amino compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, in an amount for inhibiting aromatase, and a pharmaceutically acceptable carrier.